The ultimate objectives of this proposal are to determine the role of natural resistance and the functions of the host's genetic composition in host defense against tumors. The immediate objectives of this proposal are to establish the in vivo and in vitro models for natural host resistance against murine tumors which is determined by genes linked to the host's major histocompatibility complex and to define the effectors and the nature of target antigens involved in the reactions. In the in vivo model, histocompatible F1 hybrids of DBA/2 mice with various congenic H-2 recombinant strains will be used as hosts to test their resistance against the growth of the DBA/2 lymphoma L1210 and three drug-resistant L1210 sublines. These sublines have previously been shown to have a high density of tumor-associated antigens (TAA). We will study whether the resistance of the F1 hybrids against the sublines differs from that of the L1210 and determine the effects of the host's genetic composition coded by the H-2 as well as non-H-2 loci. In the in vitro model, lymphocytes of normal histocompatible F1 hybrids will be cultured with irradiated cells of these tumors. The antibody-forming cell (AFC) and cell-mediated cytotoxic (CMC) responses will be measured by the plaque assay and the 51Cr-release cytotoxicity test, respectively, using the tumor cells as target. The in vitro results will be compared with the in vivo results. Effectors and their functions of the in vitro responses will be thoroughly characterized: cell types will be determined by the tests for surface characteristics of B cells, T cells, NK cells and macrophages, and requirements for accessory cell functions will be examined by selective depletion and reconstitution of cell preparations with the functional cell subpopulation. Hybridoma-produced monospecific antibodies directed to TAA or other relevant surface antigens on tumor cells will be used in the antibody-mediated specific suppression in attempts to identify target antigens for the in vitro responses.